Trends in Immunotherapy

Review

Molecular pathogenesis of fibrosis in systemic sclerosis

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https://doi.org/10.24294/ti.v6.i1.1453
Jinnin, M. (2022). Molecular pathogenesis of fibrosis in systemic sclerosis. Trends in Immunotherapy, 6(1). https://doi.org/10.24294/ti.v6.i1.1453
Volume 6 Issue 1 (2022)

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Authors

  • Masatoshi Jinnin
    Department of Dermatology, Graduate School of Medicine, Wakayama Medical University

The principal cause of fibrosis in systemic sclerosis is thought to be excessive deposition of extracellular matrix in multiple organs. The main component of matrix is thought to be collagen, especially type I collagen, which is one of the most abundant proteins in the mammalian body. Various factors have been estimated to be involved in the mechanism of their excessive deposition in fibrotic tissues of systemic sclerosis. In this review, we discuss the latest findings on these factors.

Keywords:

Fibroblasts Myofibroblasts Collagen

References

  1. Asano Y, Takahashi T, Saigusa R. Systemic sclerosis: Is the epithelium a missing piece of the pathogenic puzzle? Journal of Dermatological Science 2019; 94(2): 259–265. doi: 10.1016/j.jdermsci.2019.04.007
  2. Korman B. Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis. Translational Research 2019; 209: 77–89. doi: 10.1016/j.trsl.2019.02.010
  3. Leask A. Towards an anti-fibrotic therapy for scleroderma: Targeting myofibroblast differentiation and recruitment. Fibrogenesis & Tissue Repair 2010; 3: 8. doi: 10.1186/1755-1536-3-8
  4. Serrati S, Chilla A, Laurenzana A, et al. Systemic sclerosis endothelial cells recruit and activate dermal fibroblasts by induction of a connective tissue growth factor (CCN2)/transforming growth factor beta-dependent mesenchymal-to-mesenchymal transition. Arthritis & Rheumatology 2013; 65(1): 258–269. doi: 10.1002/art.37705
  5. Furue M, Mitoma C, Mitoma H, et al. Pathogenesis of systemic sclerosis-current concept and emerging treatments. Immunologic Research 2017; 65(4): 790–797. doi: 10.1007/s12026-017-8926-y
  6. Shook BA, Wasko RR, Rivera-Gonzalez GC, et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 2018; 362(6417). doi: 10.1126/science.aar2971
  7. Jinnin M. Mechanisms of skin fibrosis in systemic sclerosis. The Journal of Dermatology 2010; 37(1): 11–25. doi: 10.1111/j.1346-8138.2009.00738.x
  8. Ihn H. The role of TGF-β signaling in the pathogenesis of fibrosis in scleroderma. Archivum Immunologiae et Therapiae Experimentali 2002; 50(5): 325–331.
  9. Piersma B, Bank RA, Boersema M. Signaling in Fibrosis: TGF-beta, WNT, and YAP/TAZ Converge. Frontiers in Medicine 2015; 2: 59. doi: 10.3389/fmed.2015.00059
  10. Asano Y, Ihn H, Yamane K, et al. Impaired Smad7-Smurf-mediated negative regulation of TGF-β signaling in scleroderma fibroblasts. The Journal of Clinical Investigation 2004; 113(2): 253–264. doi: 10.1172/JCI16269
  11. Noda S, Asano Y, Nishimura S, et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nature Communications 2014; 5: 5797. doi: 10.1038/ncomms6797
  12. Wernig G, Chen SY, Cui L, et al. Unifying mechanism for different fibrotic diseases. Proceedings of the National Academy of Sciences of the United States of America 2017; 114(18): 4757–4762. doi: 10.1073/pnas.1621375114
  13. Maurer B, Busch N, Jüngel A, et al. Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis. Circulation 2009; 120(23): 2367–2376. doi: 10.1161/CIRCULATIONAHA.109.855114
  14. Takeda N, Manabe I, Uchino Y, et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. The Journal of Clinical Investigation 2010; 120(1): 254–265. doi: 10.1172/JCI40295
  15. Fujiu K, Manabe I, Nagai R. Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice. The Journal of Clinical Investigation 2011; 121(9): 3425–3441. doi: 10.1172/JCI57582
  16. Whitfield ML, Finlay DR, Murray JI, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proceedings of the National Academy of Sciences of the United States of America 2003; 100(21): 12319–12324. doi: 10.1073/pnas.163511410
  17. Pedroza M, Le TT, Lewis K, et al. STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. The FASEB Journal 2016; 30(1): 129–140. doi: 10.1096/fj.15-273953
  18. Rueda B, Broen J, Simeon C, et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Human Molecular Genetics 2009; 18(11): 2071–2077. doi: 10.1093/hmg/ddp119
  19. Bhattacharyya S, Wang W, Qin W, et al. TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung. JCI Insight 2018; 3(13): e98850. doi: 10.1172/jci.insight.98850
  20. Bhattacharyya S, Tamaki Z, Wang W, et al. FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Science Translational Medicine 2014; 6(232): 232–250. doi: 10.1126/scitranslmed.3008264
  21. Sakoguchi A, Nakayama W, Jinnin M, et al. The expression profile of the toll-like receptor family in scleroderma dermal fibroblasts. Clinical and Experimental Rheumatology 2014; 32(6 Suppl 86): S-4–9.
  22. Fang F, Marangoni RG, Zhou X, et al. Toll-like receptor 9 signaling is augmented in systemic sclerosis and elicits transforming growth factor β-dependent fibroblast activation. Arthritis & Rheumatology 2016; 68(8): 1989–2002. doi: 10.1002/art.39655
  23. Ihn H, Yamane K, Kubo M, et al. Blockade of endogenous transforming growth factor β signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: Association with increased expression of transforming growth factor β receptors. Arthritis & Rheumatology 2001; 44(2): 474–480. doi: 10.1002/1529-0131(200102)44:2<474::AID-ANR67>3.0.CO;2-%23
  24. Ihn H. Autocrine TGF-β signaling in the pathogenesis of systemic sclerosis. Journal of Dermatological Science 2008; 49: 103–113.
  25. Asano Y, Ihn H, Yamane K, et al. Involvement of αvβ5 integrin-mediated activation of latent transforming growth factor β1 in autocrine transforming growth factor β signaling in systemic sclerosis fibroblasts. Arthritis & Rheumatology 2005; 52(9): 2897–2905. doi: 10.1002/art.21246
  26. Wei J, Fang F, Lam AP, et al. Wnt/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis & Rheumatology 2012; 64(8): 2734–2745. doi: 10.1002/art.34424
  27. Sacchetti C, Bai Y, Stanford SM, et al. PTP4A1 promotes TGFbeta signaling and fibrosis in systemic sclerosis. Nature Communications 2017; 8(1): 1060. doi: 10.1038/s41467-017-01168-1
  28. Takehara K. Hypothesis: Pathogenesis of systemic sclerosis. The Journal of Rheumatology 2003; 30(4): 755–759.
  29. Fonseca C, Lindahl GE, Ponticos M, et al. A polymorphism in the CTGF promoter region associated with systemic sclerosis. The New England Journal of Medicine 2007; 357: 1210–1220. doi: 10.1056/NEJMoa067655
  30. Artlett CM, Sassi-Gaha S, Rieger JL, et al. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis & Rheumatology 2011; 63(11): 3563–3574. doi: 10.1002/art.30568
  31. Kawaguchi Y, Hara M, Wright TM. Endogenous IL-1alpha from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. The Journal of Clinical Investigation 1999; 103(9): 1253–1260. doi: 10.1172/JCI4304
  32. Salmon-Ehr V, Serpier H, Nawrocki B, et al. Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis. Archives of Dermatology 1996; 132(7): 802–806. doi: 10.1001/archderm.1996.03890310088013
  33. Postlethwaite AE, Holness MA, Katai H, et al. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. The Journal of Clinical Investigation 1992; 90(4): 1479–1485. doi: 10.1172/JCI116015
  34. Jinnin M, Ihn H, Yamane K, et al. Interleukin-13 stimulates the transcription of the human α2(I) collagen gene in human dermal fibroblasts. Journal of Biological Chemistry 2004; 279(40): 41783–41791. doi: 10.1074/jbc.M406951200
  35. Kaviratne M, Hesse M, Leusink M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. The Journal of Immunology 2004; 173(6): 4020–4029. doi: 10.4049/jimmunol.173.6.4020
  36. Hasegawa M, Sato S, Fujimoto M, et al. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. The Journal of Rheumatology 1998; 25(2): 308–313. PMID: 9489824
  37. O’Reilly S, Ciechomska M, Cant R, et al. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-beta (TGF-beta) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. Journal of Biologcial Chemistry 2014; 289(14): 9952–9960. doi: 10.1074/jbc.M113.545822
  38. Laurent P, Sisirak V, Lazaro E, et al. Innate immunity in systemic sclerosis fibrosis: Recent advances. Frontiers of Immunology 2018; 9: 1702. doi: 10.3389/fimmu.2018.01702
  39. Nakashima T, Jinnin M, Yamane K, et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. The Journal of Immunology 2012; 188(8): 3573–3583. doi: 10.4049/jimmunol.1100591
  40. Okamoto Y, Hasegawa M, Matsushita T, et al. Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis & Rheumatology 2012; 64(11): 3726–3735. doi: 10.1002/art.34643
  41. Varga J, Abraham D. Systemic sclerosis: A prototypic multisystem fibrotic disorder. The Journal of Clinical Investigation 2007; 117(3): 557–567. doi: 10.1172/JCI31139
  42. Leask A. Getting out of a sticky situation: Targeting the myofibroblast in scleroderma. The Open Rheumatology Journal 2012; 6: 163–169. doi: 10.2174/1874312901206010163
  43. Kawaguchi Y, Takagi K, Hara M, et al. Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Arthritis & Rheumatology 2004: 216–226. doi: 10.1002/art.11364
  44. Gay S, Jones Jr RE, Huang GQ, et al. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. Journal of Investigative Dermatology 1989; 92(2): 301–303.
  45. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. The New England Journal of Medicine 2006; 354(25): 2667–2676. doi: 10.1056/NEJMoa052955
  46. Higgs BW, Liu Z, White B, et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Annals of the Rheumatic Diseases 2011; 70(11): 2029–2036.
  47. Sharif R, Mayes MD, Tan FK, et al. IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. Annals of the Rheumatic Diseases 2012; 71(7): 1197–1202.
  48. Christmann RB, Sampaio-Barros P, Stifano G, et al. Association of interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis & Rheumatology 2014; 66(3): 714–725. doi: 10.1002/art.38288
  49. Kajihara I, Jinnin M, Honda N, et al. Scleroderma dermal fibroblasts overexpress vascular endothelial growth factor due to autocrine transforming growth factor β signaling. Modern Rheumatology 2013; 23(3): 516–524. doi: 10.3109/s10165-012-0698-6
  50. Maurer B, Distler A, Suliman YA, et al. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Annals of the Rheumatic Diseases 2014; 73(10): 1880–1887.
  51. Wei J, Melichian D, Komura K, et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma? Arthritis Rheum 2011; 63(6): 1707–1717.
  52. Dees C, Distler JH. Canonical Wnt signalling as a key regulator of fibrogenesis—Implications for targeted therapies? Experimental Dermatology 2013; 22(11): 710–713. doi: 10.1111/exd.12255
  53. Horn A, Palumbo K, Cordazzo C, et al. Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis & Rheumatology 2012; 64(8): 2724–2733. doi: 10.1002/art.34444
  54. Hasegawa M, Sato S, Echigo T, et al. Up regulated expression of fractalkine/CX3CL1 and CX3CR1 in patients with systemic sclerosis. Annals of the Rheumatic Diseases 2005; 64(1): 21–28.
  55. Luong VH, Utsunomiya A, Chino T, et al. Inhibition of the progression of skin inflammation, fibrosis, and vascular injury by blockade of the CX3 CL1/CX3 CR1 pathway in experimental mouse models of systemic sclerosis. Arthritis & Rheumatology 2019; 71(11): 1923–1934. doi: 10.1002/art.41009
  56. Higashi-Kuwata N, Jinnin M, Makino T, et al. Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Research & Therapy 2010; 12(4): 128. doi: 10.1186/ar3066
  57. Dumoitier N, Chaigne B, Regent A, et al. Scleroderma peripheral B lymphocytes secrete interleukin-6 and transforming growth factor beta and activate fibroblasts. Arthritis & Rheumatology 2017; 69(5): 1078–1089. doi: 10.1002/art.40016
  58. Choi MY, Fritzler MJ. Progress in understanding the diagnostic and pathogenic role of autoantibodies associated with systemic sclerosis. Current Opinion in Rheumatology 2016; 28(6): 586–594. doi: 10.1097/BOR.0000000000000325
  59. Mavropoulos A, Simopoulou T, Varna A, et al. Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis & Rheumatology 2016; 68(2): 494–504. doi: 10.1002/art.39437
  60. Fuschiotti P, Larregina AT, Ho J, et al. Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis. Arthritis & Rheumatology 2013; 65(1): 236–246. doi: 10.1002/art.37706
  61. Pincha N, Hajam EY, Badarinath K, et al. PAI1 mediates fibroblast-mast cell interactions in skin fibrosis. The Journal of Clinical Investigation 2018; 128(5): 1807–1819. doi: 10.1172/JCI99088
  62. Altorok N, Tsou PS, Coit P, et al. Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Annals of the Rheumatic Diseases 2015; 74(8): 1612–1620.
  63. Huber LC, Distler JH, Moritz F, et al. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis & Rheumatology 2007; 56(8): 2755–2764. doi: 10.1002/art.22759
  64. Wei J, Ghosh AK, Chu H, et al. The histone deacetylase sirtuin 1 is reduced in systemic sclerosis and abrogates fibrotic responses by targeting transforming growth factor β signaling. Arthritis & Rheumatology 2015; 67(5): 1323–1334. doi: 10.1002/art.39061
  65. He Y, Tsou PS, Khanna D, et al. Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. Annals of the Rheumatic Diseases 2018; 77(8): 1208–1218.
  66. Bergmann C, Brandt A, Merlevede B, et al. The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Annals of the Rheumatic Diseases 2018; 77(1): 150–158.
  67. Krämer M, Dees C, Huang J, et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Annals of the Rheumatic Diseases 2013; 72(4): 614–620.
  68. Maurer B, Stanczyk J, Jüngel A, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis & Rheumatology 2010; 62(6): 1733–1743. doi: 10.1002/art.27443
  69. Jinnin M. Recent progress in studies of miRNA and skin diseases. The Journal of Dermatology 2015; 42(6): 551–558. doi: 10.1111/1346-8138.12904
  70. Sing T, Jinnin M, Yamane K, et al. microRNA-92a expression in the sera and dermal fibroblasts increases in patients with scleroderma. Rheumatology 2012; 51(9): 1550–1556. doi: 10.1093/rheumatology/kes120